AbstractThe prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is believed to play a role in prostate cancer (PCa) progression. Cancer cells can take up lipids from the microenvironment and store them in lipid droplets (LDs). Fatty acids released from LDs are used by PCa cells as preferential metabolic fuels to provide energy and promote cancer progression. Recently, fatty acids have been associated with autophagy, a cellular recycling pathway. Lipophagy is a selective form of autophagy involved in LD degradation, the role of which in PCa progression remains unknown. Here, we explored markers of autophagy and lipophagy in human PCa tissues in correlation with factors of aggressiveness, and we evaluated the influence of PPAT adipocytes on autophagy and lipophagy. We analyzed markers of autophagy (p62, LC3), lipid droplets (PLIN and Oil Red O), androgen receptor (AR), proliferation (Ki67), and epithelial–mesenchymal transition (Zeb1) on 465 PCa samples. Co‐cultures of PCa cell lines PC3 and 22RV1 with adipocytes isolated from patients' PPAT were used to analyze the influence of PPAT on autophagy and lipophagy in vitro. In human PCa tissues, we observed a correlation between markers of LD and those of autophagy, which are associated with clinical and biological factors of disease aggressiveness. In addition, PLIN staining was associated with AR expression. In locally advanced PCa, p62, LC3, and PLIN were increased in extraprostatic areas where cancer cells are in contact with PPAT. Co‐culture of PCa cell lines with adipocytes decreased autophagy activity and increased LD flux in PC3 cells. These results suggest an active process of lipophagy in PCa, linked to disease aggressiveness, to the proximity of PPAT, and induced in vitro in co‐culture with adipocytes. Lipophagy is therefore likely to be a crucial player in PCa progression. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.